Integrative Cancer Biology & Research Clinical Effects of The
Total Page：16
File Type：pdf, Size：1020Kb
Integrative Cancer Biology & Research Research Article Open Access Keywords: Beta-carbolines; Melatonin; Palliative therapy; Clinical Effects of the Pineal Pineal gland; Pinealine Antitumor and Psychedelic Introduction Beta-Carboline Pinealine in the It is an existential evidence, but also confirmed by the recent discoveries in tumor psychoneuroendocrinoimmunology (PNEI) [1], Palliative Therapy of Untreatable that all life conditions of open mind, including spiritual meditation, Metastatic Cancer Patients sexual excitation and amplification of pleasure [2], may play an anticancer activity by either inhibiting tumore cell proliferation, or stimulating the natural immunbiological resistance against cancer 1 2 1 Giuseppe Di Fede , Giusy Messina *, Alejandra Monzon , Ornella development. This is true also for all chemical agents able to expand the 1 1 1 2 Meli , Carlo Gavazzeni , Franco Rovelli and Paolo Lissoni consciousness status, such as cannabinoids [3], pineal indole hormones 1 Institute of Biological Medicine, Milan, Italy [4] and beta-carbolines [5]. In contrast, all psychological conditions 2International Institute of Clinical Psychoneuroendocrinoimmunology, Milan, Italy characterized by a decreased consciousness state [2], including stress, anxiety, depression, psychological conflicts and unconscious self- *Corresponding author: Giusy Messina, punishment situations, as well as chemical agents reducing the status of Email: [email protected] consciousness, namely mu-opioid agonists, may promote cancer growth Received: 09 January 2017; Accepted: 03 February 2017; Published: 12 by directly stimulating cancer cell proliferation [6]. This could result February 2017 also through an inhibition of the antitumor immunity, mainly due to a stimulation of regulatory T lymphocytes (T reg) [7], which in contrast Abstract suppress the antitumor immune reaction [8]. The recent advances in the knowledge of tumor PNEI have allowed to identify the neurochemical The pineal gland has been proven to play a fundamental role in mechanisms involved in mediating the influence of the emotions and the mediating the influence of the psychospiritual status on the clinical spiritual sensibility on the anticancer immunity [1,2], which is mainly course of the neoplastic diseases. Melatonin (MLT), the most induced by IL-2 [9] and IL-12 [10] and inhibited by TGF-beta released investigated pineal hormone, has appeared to play an anticancer by T reg lymphocytes [11]. To synthetize, stress and depression would activity by either exerting a direct cytotoxic action or a stimulation inhibit the anticancer immunity mainly through an activation of brain of the anticancer immunity. However, MLT would not be the only opioid system, whereas spirituality and pleasure would stimulate the hormone responsible for the anticancer role of the pineal gland. Other anticancer immunity by activating the pineal-brain cannabinoid system pineal indole hormones, such as the 5-methoxytryptamine (5-MTT), functional axis [1-7]. On these bases, it becomes potentially possible may have anticancer activity. More recently the pineal gland has been to activate the anticancer immunity by acting not only on immune shown to represent the main source of beta-carbolines, which may system itself, but also on its physiological psychoneuroendocrine exert both psychotropic and anticancer effects. The main endogenous modulation. In fact, from this point of view, it is known since more than beta-carboline would consist of the 6-methoxy-1,2,3,4-tetrahydro- 50 years that the pineal gland plays a fundamental role in determining beta-carboline, also called pinealine. High-dose of MLT alone or in the natural resistance against cancer growth [12,13]. This, by either association with 5-MTT may induce a disease control also in patients inhibiting cancer cells proliferation [12], or stimulating the IL-2 and with disseminated cancer, and for whom no other standard antitumor IL-12-dependent anticancer immunity [13] through the release of its treatment was available. This preliminary study was performed to most investigated indole hormone, melatonin (MLT) [14] and other evaluate the effects of a concomitant association of pinealine to high- less studied antitumor molecules [15,16], namely the indole 5-methoxy- dose MLT plus 5-MTT in a group of untreatable metastatic solid tumor tryptamine (5-MTT) [15] and various beta-carbolines, the most known patients. The study included 14 consecutive patients, who were treated of them is the 6-methoxy- 1,2,3,4-tetrahydro-beta-carboline, also called orally with MLT al 100 mg/day in the night, 5-MTT at 5 mg/day at noon pinoline or pinealine (PNL) [16]. Melatonin, also known as N-acetyl- and pinealine at 1 mg/day in the evening. According to WHO criteria, 5-methoxy tryptamine, is a hormone produced by the pineal gland in the clinical response consisted of partial response (PR) in 1/14 (7%) animals, known as an antioxidant, regulator of sleep and wakefulness and a stable disease (SD) in other 9 patients. Then, a disease control (PR and with immunomodulating properties. Pinoline (6-methoxy-1,2,3,4- + SD) was achieved in 10/14 (72%) patients, whereas the remaining tetrahydro-β-carboline, usually abbreviated as 6-MeO-THBC). 4 patients had a rapid progressive disease (PD). No pinealine-related 5-Methoxytryptamine (5-MT) is a tryptamine derivative closely related biological toxicity occurred. Moreover, no hallucinatory phenomenon to the neurotransmitters serotonin and melatonin. 5-MT has been or anxiety exacerbation was observed with pinealine, at least at the shown to occur naturally in the body in low levels. It is produced by employed dose of 1 mg/day. On the contrary, most patients referred a O-metilation of the neurotransmitter N-acetylserotonine by the enzime rapid improvement of mood. Moreover, 9 patients experienced also a 5-hydroxyindole-O-methyltransferase (5-HIOMT), essential enzime in clear well-being, due to an expansion of their self-consciousness and the biosyntethic pathway of Melatonin. The biological activity of this pleasure perception. This preliminary study shows that the pineal beta- molecule is of interest as an antioxidant, and as a monoamine oxidase carboline pinealine may rapidly improve mood and self-consciousness A inhibitor. The formation of pinoline requires 5-Methoxytryptamine in patients with disseminated cancer, form whom no other standard as substrate, therefore endogenous synthesis of it is largely present in anticancer therapy may be available. Therefore, pinealine could be the pineal gland. Recent studies have also highlighted the antioxidant successfully included within the common drugs used in the palliative action and of free radical scavenger of melatonin and pinealine therapy of cancer. On the other hand, as far as the potential anticancer [17,18]. The pineal gland would constitute the main brain source of activity of pinealine is concerned, these preliminary results seem to beta-carbolines, which originate from the condensation of indole- suggest that the association of pinealine may allow a percentage of ethylamines and aldehydes and which may exert both antitumor effects disease control superior to that reported with the only pineal indoles. and psychedelic expansion of mind [19], by playing a fundamental role Further randomized studies, however, with the only pineal indoles or in self-consciousness processes and in the chemistry of the spiritual with pineal indoles plus pinealine will be required to establish whether the association of pinealine may further enhance the therapeutic Copyright © 2017 The Authors. Published by Scientific Open Access antitumor activity already exerted by the pineal indoles. Journals LLC. Di Fede et al. Volume 1, Issue 1 Integr Canc Biol Res 2017; 1:002 life, as suggested by the fact that the chemical principles of the chemotherapies. Eligibility criteria were, as follows: histologically main psychotropic plants are beta-carbolines, such as harmine and proven metastatic solid tumor, measurable lesions, no availability harmaline [20]. Moreover, beta-carbolines may induce antidepressant of other standard anticancer therapies and life expectancy less than effects because of their inhibitory activity on MAO system [16- 6 months. Tumor histotype were, as follows: colon cancer: 2; breast 20]. Unfortunately, the psychopharmacology has been substantially cancer: 2; pancreatic adenocarcinoma: 2; endometrial adenocarcinoma: applied until now only to act on the psychological life by influencing 2; small cell lung cancer: 1; hepatocarcinoma: 1; gastric cancer: 1; emotions and mood, or to control hallucinatory phenomenons, rather malignant melanoma: 1; thymic carcinoma: 1; germinoma: 1. Dominant than to directly act on the consciousness status, in an attempt to induce metastasis sites were lung in 6, peritoneum in 3, liver in 2, lung plus or to restablish the condition of self-consciousness in patients with peritoneum in 1, brain in 1, and bone in the last patient. Moreover, one self consciousness deficiency, such as in autism and schizophrenia. patient with pineal germinoma was in comatous status following brain At present, beta-carbolines are probably the less studied molecules hemorrhagic episode. The major cancer progression-related symptoms of human body. In any case, the great difficulty to understand the consisted of asthenia in 8/14 patients, depression in 5 and cachexia in effects of beta-carbolines would be due to their different molecular 6 patients. According to previous clinical studies [24-26],